Toxicity mechanisms of Aβ42 and Tau in aged cells

Aβ42 和 Tau 在衰老细胞中的毒性机制

• 批准号: 10469528
• 负责人: Chuankai Zhou
• 金额: $ 19.4万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469528
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Behavioral; Biological Aging; Biological Assay; Biological Process; CRISPR screen; Cell Culture Techniques; Cell model; Cells; Chemicals; Clinical; Clinical Trials; Cognitive deficits; Confocal Microscopy; Defect; Dementia; Deposition; Development; Disease; Disease Progression; Drosophila melanogaster; Failure; Functional disorder; Genetic; Goals; Grant; Health Benefit; Human; Intervention; Late Onset Alzheimer Disease; Left; Link; Longevity; Mammalian Cell; Methodology; Methods; Microscopic; Mitochondria; Modeling; Molecular; Neurons; Older Population; Patients; Pattern; Peptides; Persons; Physiology; Pilot Projects; Predisposition; Process; Proteins; Proteome; Research; Resistance; Resolution; Role; Saccharomyces cerevisiae; Structure; System; Tauopathies; Testing; Toxic effect; Work; Yeast Model System; Yeasts; abeta accumulation; abeta toxicity; age related; age related neurodegeneration; aged; cell age; cell type; cytotoxicity; design; fly; healthspan; hyperphosphorylated tau; insight; mitochondrial dysfunction; neuron loss; neurotoxic; normal aging; novel; novel strategies; overexpression; prevent; programs; protein expression; proteostasis; repaired; screening; successful intervention; tau Proteins

ABSTRACT Alzheimer's disease (AD) is characterized by a progressive loss of neuronal structures and functions that underlie cognitive defects and dementia. The neuronal damage has been linked to the aggregation of Aβ peptides and hyperphosphorylated Tau proteins. However, clinical results of reducing these neurotoxic proteins have been disappointing. These failures suggest that AD is a multifactorial process and that many cellular defects were left uncorrected after removing the Aβ/Tau depositions. Finding these resistant cellular defects is a critical step towards the successful intervention of AD. Studies in humans have shown that aging is the biggest risk factor for AD. However, most cellular mechanisms of Aβ/Tau toxicity are generated by research in young cells. As aged cells have different proteomes and physiology than young cells, studying the cellular toxicity of Aβ42/Tau in aged cells is a better model for their toxicity in older AD patients and is required to reveal the resistant cellular defects that are induced by Aβ42/Tau during aging. The goal of this proposal is to determine how Aβ/Tau, together with aging, changes the cellular compartmentalization and whether rejuvenating some of these defects can protect cells from the toxicity of Aβ/Tau. Identifying these age-specific Aβ/Tau sensitive targets will reveal novel mechanisms of Aβ/Tau toxicity and enable strategies to rescue cellular defects that are left uncorrected after removing the Aβ/Tau depositions. We propose to use Saccharomyces cerevisiae (yeast) and Drosophila melanogaster (fly) for this pilot project as these two model organisms are widely used to study molecular mechanisms of aging and AD. Yeast and fly share many biological processes with humans and develop age- related cellular dysfunctions similar to human aging. The yeast model of AD has been used to reveal conserved mechanisms of amyloid aggregation and the cellular toxicity of Aβ and Tau, as well as the genetic and chemical toxicity modifiers. However, these studies looked at the young yeast cells expressing the human Aβ/Tau proteins. Therefore, we want to combine the strength of aging and AD research in yeast to screen for the defects of protein expression and localization caused by Aβ42/Tau in aged cells. Our strategy is to use aged yeast to screen for hits and test the conserved ones in fly models of AD. We intend to accomplish our goal by 1) determining how Aβ and Tau proteins interfere with protein expression and localization in replicatively old yeast cells, and 2) evaluating the beneficial effect of newly identified longevity factors in fly models of AD. The yeast screen will be accomplished by using a new high-throughput microscopic screening method developed in our lab for aged cells. The insights gained from the yeast screen will also be tested in the fly models of AD. This work will advance our understanding of the interactions between aging and AD-related proteins that together cause the age-related neurodegenerative diseases.

抽象的 阿尔茨海默氏病（AD）的特征是神经元结构和功能的程序丧失， 认知缺陷和痴呆症的基础与Aβ的聚集有关 然而，肽和熟悉的tau蛋白。 这些失败令人失望。 除去Aβ/TAU沉积后，未纠正。 朝着人类研究成功干预的一步表明Ging是最大的风险 但是，AD的因素。 由于老化的细胞具有与幼小细胞不同的蛋白质组和生理学，因此研究Aβ42/tauu的细胞毒品 在老年细胞中，是老年AD患者毒性的更好模型，需要揭示耐药性细胞 衰老过程中Aβ42/tau诱导的缺陷。 与衰老一起，改变了细胞分区化，并使其中一些缺陷恢复活力 可以保护细胞免受Aβ/TAU的毒性侵害。 Aβ/TAU毒性的新型机制，并使策略能够恢复不正确的餐馆缺陷 去除Aβ/tau沉积后，我们建议使用酿酒酵母（酵母）和果蝇 该试点项目的Melanogaster（Fly），因为模型生物无限于研究分子 衰老和酵母机制。 相关的细胞功能障碍与人类衰老相似。 淀粉样蛋白聚集的机理和Aβ和TAU的细胞毒品 然而，这些研究着眼于表达人Aβ/tau蛋白的酵母细胞。 因此，我们想结合酵母中衰老和AD研究的强度，以筛选蛋白质缺陷 Aβ42/tau在老年细胞中引起的表达和定位。 命中和测试AD的飞行模型中的保守速度。 Aβ和tau蛋白会干扰复制旧酵母细胞中的蛋白质表达和定位，2） 评估酵母屏幕飞行模型中新确定的寿命因子的有益。 通过使用在我们实验室为老年细胞中开发的新的高通量显微镜筛选方法来完成。 从屏幕上获得的见解Willen Willo在AD的飞行模型中被测试。 了解衰老和与AD相关的蛋白之间的相互作用，这些蛋白在一起引起与之相关的蛋白质 神经退行性疾病。

项目成果

Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.

• DOI: 10.7554/elife.75658
• 发表时间: 2022-03-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Liu Q;Chang CE;Wooldredge AC;Fong B;Kennedy BK;Zhou C
• 通讯作者: Zhou C

Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.

• DOI: 10.1073/pnas.2300475120
• 发表时间: 2023-08
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Liu, Qingqing;Fong, Benjamin;Yoo, Seungmin;Unruh, Jay R.;Guo, Fengli;Yu, Zulin;Chen, Jingjing;Si, Kausik;Li, Rong;Zhou, Chuankai
• 通讯作者: Zhou, Chuankai